Influenza virus represents a serious public health threat not only with regard to epidemic influenza but also due to the ever-increasing threat of highly virulent pandemic outbreaks. The clearance of primary influenza virus infections is largely thought to be mediated through influenza-specific CD8 T cells, which promote recovery from infection by the killing of influenza-infected cells. Historically, the immune mechanisms responsible for eliminating influenza infections were dependent on perforin and FasL-mediated responses, but recent studies have suggested that CD8 T cells can also trigger apoptosis in virus-infected cells via a TRAIL-dependent mechanism. Notably, our understanding of the involvement of TRAIL in immune responses to influenza-virus is quite limited. Therefore our long-term goal is to delineate the role of TRAIL in influenza-specific immunity with an eye toward the design of protective vaccines and elicitation of effective immune responses against this important human pathogen. Our initial studies have demonstrated that the absence of TRAIL expression during influenza infections increases pulmonary virus titers, morbidity and disease severity and decreases virus- specific cytotoxicity. Further TRAIL and DR5 (i.e. TRAIL receptor 2) expression are significantly upregulated in the lungs of wild type mice following influenza virus infections. This expression appears to correlate with virus elimination and the influx of TRAIL+IFN?+ influenza-specific CD8 T cells into the lungs, suggesting that TRAIL/DR5 (i.e. CD8 T cell/infected cell) interactions could be an integral part in the development of protective immunity to influenza virus. Therefore in this proposal we will utilize both our murine model of influenza virus infection and in vitro infection of human lung cells to determine what role TRAIL expression has in immunity to influenza infections. Specifically, we will address and resolve this question using the following Aims: 1) Determine if TRAIL deficiency alters pulmonary virus clearance, influenza antigen load, and influenza-specific CD8 T cell responses and 2) Determine the mechanism by which influenza infection sensitizes lung cells to TRAIL. This proposal will not only increase our understanding of the immune response to influenza virus infections but also elucidate how TRAIL expression/deficiency may alter the virulence of influenza virus infections. This knowledge will be relevant not only to our understanding of the mechanisms allowing elimination of virus infections in the lungs but also in the design of methods to combat epidemic or pandemic influenza outbreaks. Project Narrative: During epidemic and pandemic influenza, CD8 T cell responses are known to kill influenza-infected cells allowing clearance of the virus and recovery. Recently it has been reported that CD8 T cells can utilize TRAIL, in addition to perforin and FasL, to mediate the killing of virus infected cells. This project will increase our understanding of the role of TRAIL in influenza-specific immune elimination of virus infections of the lungs and therefore aid us in the design of strategies to combat epidemic or pandemic influenza outbreaks. [unreadable] [unreadable] [unreadable]